This application proposes to use PBMC specimens collected from two ACTG protocols to retrospectively study clonal expansions in the CD4 lymphocyte repertoire that occur in HIV infection and their response(s) to HAART. The PI has recently identified large clonal/oligoclonal expansions in CD4 cells in a limited number of patients with HIV. Previous work by the PI has shown that clonal expansions of CD4 cells in the periphery are not found in a large sampling of 147 healthy children and adults, from a broad range of ages, or in autoimmune disease states, such as rheumatoid arthritis. Therefore, such clonal CD4 cell expansions may be unique to HIV infection. It is hypothesized that the expanded CD4 cell clones arise from proliferation to specific HIV antigens, but they have been rendered functionally deficient by the disease process. The goal of this proposal is to determine the clonal or oligoclonal nature of CD4 cell subsets that express particular TCR V-beta determinants in HIV patients, prior to therapy and following up to 80 weeks of HAART. Subsets representing both expanded and non- expanded V-beta phenotypes will be analyzed to: 1) compare their proliferative capacity in vitro, 2) determine changes in TCR diversity following HAART, and 3) derive TCR sequences to be expressed in a transgenic hybridoma cell model to screen for specific reactivity to HIV antigen epitopes. In addition, experiments will be done to determine whether expanded subsets of CD4 cells harbor increased HIV DNA load in comparison to non-expanded subsets, and whether any differential levels in viral DNA persist following extended HAART.